Manufacturing Technology Committee – Risk Management Working Group

Risk Management Case Studies

Functional Equivalence for Equipment

Case Study Title: Case No. RMWG-03
Replacements
GMP System
Facilities and Engineering
Impacted:
Pharmaceutical manufacturers have an obligation to ensure that their
manufacturing equipment is properly designed, installed, tested, operated, and
Introduction / maintained throughout their service lifetimes. During these service lifetimes
manufacturing equipment will likely require both preventive and corrective
Background maintenance activities that may involve the replacement of parts within the
systems. Parts replacements must be performed under the appropriate change
controls to ensure that manufacturing equipment remains in a validated state with
respect to installation, operation, and performance. Change control
considerations are greatly facilitated when replacement parts are exactly identical
to the original parts. However, it is not uncommon for pharmaceutical
manufacturers to resort to procuring and installing replacement parts that are not
identical to the original parts due to changes affected by parts suppliers (product
redesigns, discontinuations, etc.). In these instances, a risk management
approach may be utilized to systematically assess whether replacement parts are
functionally equivalent (also referred to as like-for-like) with original parts in order
to ensure proper change control while also preventing unnecessary revalidation
activities.

In this case study, a risk management approach was taken by the firm to identify
the following:
Risks associated with equipment parts changes that might adversely
impact the validated state of manufacturing equipment
Risks associated with the process of determining whether original and
replacement parts are functionally equivalent
Proper roles and responsibilities of the functional areas involved in the
process of determining whether original and replacement parts are
functionally equivalent

The outputs of the risk management approach utilized by the firm included a
generic, robust, and repeatable process for performing functional equivalence
assessments as well as definition of organizational roles and responsibilities
supporting the process.

Defining the Risk The risk question developed for the subject case study is:
Question
What process and associated functional area roles and responsibilities
are required in order to assess whether replacement parts are
functionally equivalent with original parts in order to ensure proper
manufacturing equipment change control while also preventing
unnecessary revalidation activities?
Case Study: Functional Equivalence for Equipment Replacements (Study # RMWG-03)

Selecting a Risk In this case study, the firm elected to craft one risk assessment for the overall
Assessment (generic) functional equivalence assessment process in order to achieve two
Method objectives:

Identify potential gaps, inconsistencies, and redundancies within the

process that had historically been used for replacement parts functional
equivalence determinations.

Identify new or improved activities that would lead to robust, efficient, and
consistent functional equivalence assessments moving forward

In order to support selection of a risk assessment method, the risk assessment

team examined the risk question (above) and also identified the core activities
supporting the historical functional equivalence assessment process as the basis
for the risk assessment. The core activities that the team examined included the
equipment change control process and the maintenance systems inventory
process control flow. Upon these examinations, the team noted the following
observations regarding the process that had historically been used for
replacement parts functional equivalence determinations:

The functional equivalence assessment process was historically

dependent upon human judgment, expertise, and experience

Process risks (potential breakdowns of the process) were qualitative in

nature, and were difficult to quantify with specificity

Given these observations, the risk assessment team selected Fault Tree Analysis
(FTA) as the risk assessment method since it is well suited for analysis of
qualitative fault conditions that may be related to human performance factors.

The risk methodology selected for the subject case study is:

Fault Tree Analysis (FTA)

Risk Assessment The risk assessment process began with a review and analysis of the change
(Risk control system to determine how equipment parts replacements could potentially
Identification, cause an unwanted or undetected change to the equipment’s validated state.
The analysis was organized into the fault tree structure depicted below in Figure
Analysis and 1. This fault tree illustrates the potential means by which equipment changes
Evaluation) such as parts replacements could pose risk to the validated state of the
equipment. The team concluded that many of the potential fault pathways were
already being appropriately mitigated by robust quality systems (such as training,
validation, and change control) that were performing as intended and are
routinely audited. However, significant gaps and improvement opportunities were
noted around the process utilized for the functional equivalence assessments
(indicated by the yellow pathway in Figure 1).

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Case Study: Functional Equivalence for Equipment Replacements (Study # RMWG-03)

Figure 1 - Fault Tree Analysis of Equipment Changes and Associated Validation Impact

Equipment change causes unwanted or

undetected change to the equipment’s
validated state

OR

Equipment change Equipment change deemed Equipment change NOT deemed

performed without being Equipment change
incorrectly assessed as functionally equivalent, but functionally equivalent, but
properly assessed for inadequate follow-up fails to change control is inadequate (ex:
functional equivalence functionally equivalent
maintain the validated state change control plan doesn’t
(ex: validation documents verify that the change was
not updated properly) executed successfully)
OR

Personnel make Personnel make change to Out of Scope - Out of Scope -

Significant gaps Adequately Adequately
inappropriate change to GMP system without going and improvement
the system’s Bill of through change control addressed by addressed by
opportunities Validation Quality Change Control
Materials (BOM) without
going through System * Quality System *
appropriate change
control OR

Maintenance Manufacturing Detail carried to next

personnel make personnel make
inappropriate inappropriate level of the fault tree
equipment change equipment change
during equipment during processing (see Figure 2)
maintenance operations
No action required -
adequately
addressed by * Quality Systems are performing as intended and are robust
Training Quality as verified through regular auditing. Team unanimously
System * agrees that these risks have low probabilities of occurring

In order to further explore the risks associated with the functional equivalence
assessment process for equipment replacement parts, the risk assessment team
continued development of the fault tree as depicted below in Figure 2. The team
focused on two key areas of risk: functional equivalence assessments performed
by parts vendors, and functional equivalence assessments performed internally
by the firm’s different functional areas.

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Case Study: Functional Equivalence for Equipment Replacements (Study # RMWG-03)

Figure 2 - Fault Tree Analysis of Functional Equivalence Assessments

Equipment change
incorrectly assessed as
functionally equivalent

OR

Equipment vendor Internal functional

functional equivalence equivalence assessment is
assessment is incorrect incorrect

OR

OR
Vendor is supplied
with incorrect Vendor bias, business
equipment information pressures, incomplete Change initiator
GMP assessment, poor contributes to Technical Quality Product license
Engineering:
support due to merger/ incorrect functional Services: Assurance: impact
Incorrect
acquisition history equivalence Incorrect Incorrect assessment not
functional
OR assessment functional functional performed
equivalence
equivalence equivalence incorrectly
assessment
assessment assessment

Vendor is supplied Initiator supplies

incorrect specifications Vendor provided wrong data for
(ex: aged part with no incorrect information functional Create Create Technical Create Quality Create
existing specification from their supplier equivalence Engineering Services Assurance Regulatory
sheets) assessment assessment assessment assessment assessment
checklist checklist checklist checklist

Define Initiator
Define Initiator Out of Scope - qualifications and
qualifications and Covered in training
training Vendor Audit requirements
requirements System *

* Quality System is performing as intended and is robust as

verified through regular auditing. Team unanimously agrees
that these risks have low probabilities of occurring

The detailed fault tree analysis executed by the risk assessment team revealed
two areas of significant risk where improvement was required:

The Initiator (petitioner and preliminary data collector) for functional

equivalence evaluations should be a Subject Matter Expert (SME) that is
appropriately trained and qualified to craft accurate initial assessments
(see green triangles in Figure 2).

Specific roles and responsibilities for each functional area participating in

functional equivalence assessments should be clearly defined (see beige
triangles in Figure 2).

Risk Control For each of the two areas of significant risk identified in the FTAs and
summarized above, associated risk control plans were established.

Training curricula were established to define the training and qualification

criteria for personnel initiating functional equivalence assessments.
These controls were designed to ensure that Initiators would be able to
identify, compile, and/or generate the data and rationale required to
support thorough and accurate functional equivalence assessments.

Roles and responsibilities for each functional area participating in

functional equivalence assessments were delineated in the form of
executable checklists designed to ensure that every functional
equivalence assessment will be performed in a thorough and reproducible

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Case Study: Functional Equivalence for Equipment Replacements (Study # RMWG-03)

fashion. Each organization identified in Figure 2 (Engineering, Technical

Services, Quality Assurance, and Regulatory) created a checklist tailored
to their specific roles and responsibilities that the team had collectively
defined. This approach minimized both gaps and redundancies in the
assessment efforts, while providing a common assessment record format
to facilitate overall review of the assessment package. Each functional
area checklist details unique areas of consideration for the assessment
and provides spaces for the assessment conclusions and the signatures
of the assessor(s). An example checklist from the Engineering functional
area is shown below in Figure 3

Figure 3 – Engineering Functional Equivalence Determination Checklist

Areas of Consideration Typical Characteristics of Assessment Performed
Functionally Equivalent Parts By
Materials of construction
and ratings
Composition of Comparable materials of construction
process-contact for wetted surfaces
parts
Compatibility with Parts designed to operate at expected
process process extremes (heat, pressure,
chemistry, etc.)
Surface finishes Comparable surface finishes that
support continued effective cleaning
and/or sterilization
Inputs, outputs, capacity
and performance
characteristics
Materials / flows Similar mass-transfer characteristics
(volume, pumping, friction loss,
pressure drop, etc.)
Electrical Similar electrical service requirements
and electrical performance
characteristics (resistance, frequency,
voltage)
Data Data receipt and/or transmission in the
same format (units, file types, etc.) and
with similar performance
characteristics (reporting frequency,
speed, etc.)
Sizes Comparable sizes (ex: inlet size,
nominal hold capacity, outlet size)
Metrology Measurement tolerances, scales, and
units that meet process specifications
and are comparable
System connections
Units (for Part connections that allow for receipt
instruments, control and/or transmission of data in the same
systems) format (units, file types, etc.) and with
the similar performance characteristics
Orientation (for Parts are physically configured (as
hardware) and constructed and as installed) in a
configurations comparable manner so as to continue
to meet process specifications and
support process performance (ex: flow,
drainability, cleanability, sterilization,
etc.)
Sizes / locations Parts utilize the same system
connections in the facility
Specifications (general)
Mechanisms of Parts have comparable mechanisms of
action action (ex: sequence of operations,
purported usage, design and operating
principles, etc.)
Operational ranges Parts feature comparable operational
ranges across all process parameters

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Case Study: Functional Equivalence for Equipment Replacements (Study # RMWG-03)

Risk The outputs of this risk management effort comprise the documented justification
Documentation for controlled revisions to:
and
Training and qualification curricula for personnel initiating change controls
Communication
where functional equivalence will be assessed
Equipment change control SOPs that direct the functional equivalence
assessment process for parts replacements
Maintenance systems inventory process control flow
Training is required to be performed on these updated documents and training
records are periodically audited for compliance.
Risk Review As part of the firm's standard practice for the ongoing maintenance of quality
systems, routine audits and document reviews are performed throughout each of
the quality systems impacted by this risk assessment (in this case training,
change control, and equipment maintenance). Adverse findings or trends
identified during these reviews would provide indication whether the risk
assessment needs to be revised.

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